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Clinical Trial Results:
A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 111 in Children with Achondroplasia

Summary
EudraCT number	2013-004137-32
Trial protocol	GB FR
Global end of trial date	02 Oct 2017

Results information
Results version number	v1(current)
This version publication date	27 Jun 2019
First version publication date	27 Jun 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

111-202

ISRCTN number

US NCT number

NCT02055157

WHO universal trial number (UTN)

Sponsor organisation name

BioMarin Pharmaceutical Inc.

Sponsor organisation address

105 Digital Drive, Novato, CA, United States, 94949

Public contact

Clinical Trials Information, BioMarin Pharmaceutical Inc., medinfo@bmrn.com

Scientific contact

Clinical Trials Information, BioMarin Pharmaceutical Inc., medinfo@bmrn.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-002033-PIP01-16

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

12 Oct 2018

Is this the analysis of the primary completion data?

Yes

Primary completion date

02 Oct 2017

Global end of trial reached?

Yes

Global end of trial date

02 Oct 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the initial 6-month phase is: To evaluate the safety and tolerability of daily Subcutaneous (SC) injections of BMN 111 administered for 6 months The primary objective of the study extension is: To evaluate the safety and tolerability of daily Subcutaneous (SC) injections of BMN 111 administered for up to 24 months

Protection of trial subjects

This clinical study was designed, conducted, recorded, and reported in compliance with the principles of Good Clinical Practice (GCP) guidelines. These guidelines are stated in U.S. federal regulations as well as “Guidance for Good Clinical Practice,” International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Jan 2014

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

1 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

France: 2

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

United States: 22

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study was conducted at 9 study centers in United States, Australia, United Kingdom and France.

Screening details

Of the 35 subjects enrolled to study, 32 subjects completed the initial six months and 30 completed the eighteen months extension.

Period 1 title

Initial 6 months

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Cohorts 1

Arm description

BMN 111 at 2.5 μg/kg daily subcutaneous injection, over a period of 6 months.

Arm type

Experimental

Investigational medicinal product name

BMN 111

Investigational medicinal product code

Other name

Vosoritide

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BMN 111 at 2.5 μg/kg daily subcutaneous injection, over a period of 6 months.

Cohorts 2

Arm description

BMN 111 at 7.5 μg/kg daily subcutaneous injection, over a period of 6 months.

Arm type

Experimental

Investigational medicinal product name

BMN 111

Investigational medicinal product code

Other name

Vosoritide

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BMN 111 at 7.5 μg/kg daily subcutaneous injection, over a period of 6 months.

Cohorts 3

Arm description

BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 6 months.

Arm type

Experimental

Investigational medicinal product name

BMN 111

Investigational medicinal product code

Other name

Vosoritide

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 6 months.

Cohorts 4

Arm description

BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 6 months.

Arm type

Experimental

Investigational medicinal product name

BMN 111

Investigational medicinal product code

Other name

Vosoritide

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 6 months.

Number of subjects in period 1	Cohorts 1	Cohorts 2	Cohorts 3	Cohorts 4
Started	8	8	10	9
Completed	7	7	10	8
Not completed	1	1	0	1
Consent withdrawn by subject	1	-	-	-
Subject D/C due to PI decision	-	1	-	-
Subject D/C due to AE	-	-	-	1

Period 2 title

18-month extension

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Cohorts 1

Arm description

BMN 111 at 2.5 μg/kg daily subcutaneous injection, dose determined to be suboptimal after the end of the initial 6 months, 7 subjects escalated to 7.5 μg/kg daily subcutaneous injection, discontinued 1 subject escalating 6 subjects to BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.

Arm type

Experimental

Investigational medicinal product name

BMN 111

Investigational medicinal product code

Other name

Vosoritide

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BMN 111 at 7.5 μg/kg daily subcutaneous injection, dose determined to be suboptimal after the end of the initial 6 months, discontinued 1 subject escalating 6 subjects to BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.

Cohorts 2

Arm description

Arm type

Experimental

Investigational medicinal product name

BMN 111

Investigational medicinal product code

Other name

Vosoritide

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Cohorts 3

Arm description

BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.

Arm type

Experimental

Investigational medicinal product name

BMN 111

Investigational medicinal product code

Other name

Vosoritide

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.

Cohorts 4

Arm description

BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 18 months.

Arm type

Experimental

Investigational medicinal product name

BMN 111

Investigational medicinal product code

Other name

Vosoritide

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 18 months.

Number of subjects in period 2	Cohorts 1	Cohorts 2	Cohorts 3	Cohorts 4
Started	7	7	10	8
Completed	6	6	10	8
Not completed	1	1	0	0
Subject D/C due to growth plates closure	-	1	-	-
Consent withdrawn by subject	1	-	-	-

Baseline characteristics

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Reporting group title

Cohorts 1

Reporting group description

BMN 111 at 2.5 μg/kg daily subcutaneous injection, over a period of 6 months.

Reporting group title

Cohorts 2

Reporting group description

BMN 111 at 7.5 μg/kg daily subcutaneous injection, over a period of 6 months.

Reporting group title

Cohorts 3

Reporting group description

BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 6 months.

Reporting group title

Cohorts 4

Reporting group description

BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 6 months.

Reporting group values	Cohorts 1	Cohorts 2	Cohorts 3	Cohorts 4	Total
Number of subjects	8	8	10	9
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	7.3 ± 1.58	8.3 ± 2.19	8.0 ± 1.63	6.9 ± 1.17	-
Gender categorical
Units: Subjects
Female	5	3	6	5	19
Male	3	5	4	4	16
Ethnicity
Units: Subjects
Not Hispanic or Latino	8	8	9	7	32
Hispanic or Latino	0	0	1	1	2
Not Reported	0	0	0	1	1
Race
Units: Subjects
White	7	6	5	6	24
Asian	0	1	3	3	7
Black or African American	1	0	1	0	2
Other	0	1	1	0	2
Weight
Units: kg
arithmetic mean (standard deviation)	18.58 ± 2.223	22.50 ± 4.099	25.13 ± 5.736	19.59 ± 2.859	-
Body Mass Index
Units: kg/m2
arithmetic mean (standard deviation)	20.13 ± 2.089	21.78 ± 2.1	22.21 ± 2.694	20.44 ± 1.038	-

End points

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Reporting group title

Cohorts 1

Reporting group description

BMN 111 at 2.5 μg/kg daily subcutaneous injection, over a period of 6 months.

Reporting group title

Cohorts 2

Reporting group description

BMN 111 at 7.5 μg/kg daily subcutaneous injection, over a period of 6 months.

Reporting group title

Cohorts 3

Reporting group description

BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 6 months.

Reporting group title

Cohorts 4

Reporting group description

BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 6 months.

Reporting group title

Cohorts 1

Reporting group description

Reporting group title

Cohorts 2

Reporting group description

Reporting group title

Cohorts 3

Reporting group description

BMN 111 at 15.0 μg/kg daily subcutaneous injection, over a period of 18 months.

Reporting group title

Cohorts 4

Reporting group description

BMN 111 at 30.0 μg/kg daily subcutaneous injection, over a period of 18 months.

Subject analysis set title

Cohort 1

Subject analysis set type

Safety analysis

Subject analysis set description

Safety Analysis Population includes all subjects who received at least one dose of study treatment and were used for safety analysis in the initial 6-month period and entire study period.

Subject analysis set title

Cohort 2

Subject analysis set type

Safety analysis

Subject analysis set description

Safety Analysis Population includes all subjects who received at least one dose of study treatment and were used for safety analysis in the initial 6-month period and entire study period.

Subject analysis set title

Cohort 3

Subject analysis set type

Safety analysis

Subject analysis set description

Safety Analysis Population includes all subjects who received at least one dose of study treatment and were used for safety analysis in the initial 6-month period and entire study period.

Subject analysis set title

Cohort 4

Subject analysis set type

Safety analysis

Subject analysis set description

Safety Analysis Population includes all subjects who received at least one dose of study treatment and were used for safety analysis in the initial 6-month period and entire study period.

Primary: Number of subjects with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs)

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End point title

Number of subjects with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs) ^[1]

End point description

Safety Analysis Population includes all subjects who received at least one dose of study treatment and were used for safety analysis in the initial 6-month period and entire study period. SAE (Serious Adverse Event). AE (CTCAE) Grade: 1=Mild, 2=Moderate, 3=Severe or Undesirable, 4=Life Threatening or Debilitating.

End point type

Primary

End point timeframe

Up to Month 24 ± 14 Days

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Statistical Results were summarized by dose cohort and for all cohorts combined.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	8	8	10	9
Units: Number of subjects analysed
Any Study Drug-Related AE—Grade 1	7	7	9	9
Any Study Drug-Related AE—Grade 2	0	1	0	0
Any Study Drug-Related AE—Grade 3	0	0	0	0
Any Study Drug-Related AE—Grade 4	0	0	0	0
Subjects with at Least 1 Reported TEAE	8	8	10	9
At Least 1 Reported Study Drug-Related TEAE	7	8	9	9
Subjects with at Least 1 Reported SAE	1	0	1	1
At Least 1 Reported Study Drug-Related SAE	0	0	0	0
Permanently Discontinued Study Drug due to TEAE	0	0	0	1
Subjects Who Discontinued Study due to TEAE	0	0	0	0
Subjects Who Died	0	0	0	0

No statistical analyses for this end point

Secondary: Change From Baseline of Annualized Growth Velocity (AGV) during Initial 6-Month

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End point title

Change From Baseline of Annualized Growth Velocity (AGV) during Initial 6-Month

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Annualized Growth Velocity assessed by anthropometric measurements and measurement ratios. Anthropometric measurements included standing height, sitting height, weight, head circumference, upper and lower arm and leg, hand and foot. Ratios calculated of Upper arm to forearm length ratio, Upper leg to lower leg length ratio, Upper to lower body segment ratio. Weight was measured at Screening and at each in-clinic dosing visit.

End point type

Secondary

End point timeframe

At 6 month (Day 183)

End point values	Cohorts 1	Cohorts 2	Cohorts 3	Cohorts 4
Number of subjects analysed	8	8	10	8
Units: cm/year
arithmetic mean (standard deviation)
Baseline of Initial 6-Month Period (N = 8,8,10,8)	3.755 ± 1.1094	2.891 ± 1.3920	4.044 ± 2.2751	4.492 ± 1.1889
Change from Baseline to Day 183 (N = 7,8,10,8)	-0.371 ± 1.5920	1.276 ± 1.4387	2.014 ± 1.9990	2.085 ± 2.1375

No statistical analyses for this end point

Secondary: Change From Baseline of Annualized Growth Velocity (AGV) during Entire Study Period Cohort 3 and 4

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End point title

Change From Baseline of Annualized Growth Velocity (AGV) during Entire Study Period Cohort 3 and 4

End point description

End point type

Secondary

End point timeframe

At month 24

End point values	Cohorts 3	Cohorts 4
Number of subjects analysed	10	8
Units: cm/year
arithmetic mean (standard deviation)
Baseline (N= 10,8)	4.044 ± 2.2751	4.492 ± 1.1889
Change from Baseline to Month 24 (N= 10,8)	1.744 ± 1.7974	1.538 ± 1.3387

No statistical analyses for this end point

Secondary: Change From Baseline of Annualized Growth Velocity (AGV) during Entire Study Period - Cohort 1 and 2 Switchers

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End point title

Change From Baseline of Annualized Growth Velocity (AGV) during Entire Study Period - Cohort 1 and 2 Switchers

End point description

End point type

Secondary

End point timeframe

At month 24

End point values	Cohorts 1	Cohorts 2
Number of subjects analysed	6	6
Units: cm/year
arithmetic mean (standard deviation)
Baseline (N = 6,6)	3.629 ± 1.1586	3.510 ± 0.8327
Change from Baseline at >=12 Mos on 15μg/kg(N=3,6)	1.846 ± 2.1466	2.245 ± 0.9176

No statistical analyses for this end point

Secondary: Change From Baseline of Z-Scores Using CDC Reference Standard during 6-Months Post-Treatment

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End point title

Change From Baseline of Z-Scores Using CDC Reference Standard during 6-Months Post-Treatment

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Height and Weight Z-Scores includes conversion of Height and weight to age-and sex-appropriate standard score (SDS), also referred to as Z-score by comparison with reference standards (non-ACH) derived from average-stature children from the Centers for Disease Control and Prevention (CDC) database.

End point type

Secondary

End point timeframe

At month 6 (Day 183)

End point values	Cohorts 1	Cohorts 2	Cohorts 3	Cohorts 4
Number of subjects analysed	8	8	10	8
Units: z score
arithmetic mean (standard deviation)
Baseline (n = 7,8,10,8)	-6.056 ± 0.6331	-5.145 ± 0.8530	-4.613 ± 1.1355	-5.193 ± 0.7486
Change from Baseline to Day 183 (n = 7,8,10,8)	-0.008 ± 0.1788	0.078 ± 0.1440	0.229 ± 0.1505	0.265 ± 0.1869

No statistical analyses for this end point

Secondary: Change From Baseline of Height Z-Scores Using CDC Reference Standard during Entire Study Period - Cohort 3 and 4

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End point title

Change From Baseline of Height Z-Scores Using CDC Reference Standard during Entire Study Period - Cohort 3 and 4

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Height and Weight Z-Scores includes conversion of Height and weight to age-and sex-appropriate standard score (SDS), also referred to as Z-score by comparison with reference standards (non-ACH) derived from average-stature children from the Centers for Disease Control and Prevention (CDC) database.

End point type

Secondary

End point timeframe

At month 24

End point values	Cohorts 3	Cohorts 4
Number of subjects analysed	10	8
Units: z score
arithmetic mean (standard deviation)
Baseline (n = 10, 8)	-4.613 ± 1.1355	-5.193 ± 0.7486
Change from Baseline to Month 24 (n = 10, 8)	0.788 ± 0.2842	0.896 ± 0.3010

No statistical analyses for this end point

Secondary: Change From Baseline of Height Z-Scores Using Non-ACH References during Entire Study Period - Cohort 1 and 2 Switchers

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End point title

Change From Baseline of Height Z-Scores Using Non-ACH References during Entire Study Period - Cohort 1 and 2 Switchers

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Height and Weight Z-Scores includes conversion of Height and weight to age-and sex-appropriate standard score (SDS), also referred to as Z-score by comparison with reference standards (non-ACH) derived from average-stature children from the Centers for Disease Control and Prevention (CDC) database. Mos (Months)

End point type

Secondary

End point timeframe

At month 24

End point values	Cohorts 1	Cohorts 2
Number of subjects analysed	6	6
Units: z score
arithmetic mean (standard deviation)
Baseline (n = 6,6)	-6.064 ± 0.6932	-4.912 ± 0.7708
Change from Baseline to >=12 Mos on 15ug/kg(n=3,6)	0.520 ± 0.2950	0.259 ± 0.1887

No statistical analyses for this end point

Secondary: Change From Baseline of Weight Z-Scores Using Non-ACH References during Entire Study Period - Cohort 1 and 2 Switchers

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End point title

Change From Baseline of Weight Z-Scores Using Non-ACH References during Entire Study Period - Cohort 1 and 2 Switchers

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Height and Weight Z-Scores includes conversion of Height and weight to age-and sex-appropriate standard score (SDS), also referred to as Z-score by comparison with reference standards (non-ACH) derived from average-stature children from the Centers for Disease Control and Prevention (CDC) database. Mos (Months)

End point type

Secondary

End point timeframe

At month 24

End point values	Cohorts 1	Cohorts 2
Number of subjects analysed	6	6
Units: z score
arithmetic mean (standard deviation)
Baseline (n = 6,6)	-2.615 ± 0.9648	-1.436 ± 0.3942
Change from Baseline to >=12 Mos on 15ug/kg(n=3,6)	0.926 ± 0.2311	0.173 ± 0.1287

No statistical analyses for this end point

Secondary: Change From Baseline of Upper to Lower Body Ratios during 6 Months Post Treatment

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End point title

Change From Baseline of Upper to Lower Body Ratios during 6 Months Post Treatment

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.

End point type

Secondary

End point timeframe

At month 6 and month 24

End point values	Cohorts 1	Cohorts 2	Cohorts 3	Cohorts 4
Number of subjects analysed	8	8	10	8
Units: Ratio
arithmetic mean (standard deviation)
Baseline (n = 7,8,10,8)	2.094 ± 0.0984	2.027 ± 0.1793	1.911 ± 0.2286	1.962 ± 0.1822
Change from Baseline to Day 183 (n = 7,8,10,8)	-0.021 ± 0.0626	0.003 ± 0.0510	-0.024 ± 0.0369	-0.030 ± 0.0811

No statistical analyses for this end point

Secondary: Change From Baseline of Upper to Lower Body Ratios during Entire Study Period - Cohort 3 and 4

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End point title

Change From Baseline of Upper to Lower Body Ratios during Entire Study Period - Cohort 3 and 4

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.

End point type

Secondary

End point timeframe

At month 24

End point values	Cohorts 3	Cohorts 4
Number of subjects analysed	10	8
Units: ratio
arithmetic mean (standard deviation)
Baseline (n= 10,8)	1.911 ± 0.2286	1.962 ± 0.1822
Change from Baseline to Month 24 (n= 10,8)	-0.067 ± 0.0451	-0.121 ± 0.1058

No statistical analyses for this end point

Secondary: Change From Baseline of Upper Arm to Lower Arm Length Ratio during 6 Months Post Treatment - Cohort 3 and 4

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End point title

Change From Baseline of Upper Arm to Lower Arm Length Ratio during 6 Months Post Treatment - Cohort 3 and 4 ^[2]

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.

End point type

Secondary

End point timeframe

At month 6 (Day 183) and 24

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical Results were summarized by dose cohort and for all cohorts combined.

End point values	Cohorts 3	Cohorts 4
Number of subjects analysed	10	8
Units: ratio
arithmetic mean (standard deviation)
Baseline (n = 10,8)	1.130 ± 0.1190	1.106 ± 0.0816
Change from Baseline to Day 183 (n = 10,8)	-0.048 ± 0.1002	0.003 ± 0.0869

No statistical analyses for this end point

Secondary: Change From Baseline of Upper Arm to Lower Arm Length Ratio during Entire Study Period - Cohort 3 and 4

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End point title

Change From Baseline of Upper Arm to Lower Arm Length Ratio during Entire Study Period - Cohort 3 and 4

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.

End point type

Secondary

End point timeframe

At month 24

End point values	Cohorts 3	Cohorts 4
Number of subjects analysed	10	8
Units: ratio
arithmetic mean (standard deviation)
Baseline (n = 10,8)	1.130 ± 0.1190	1.106 ± 0.0816
Change from Baseline to Month 24 (n = 10,8)	0.037 ± 0.0673	-0.027 ± 0.0504

No statistical analyses for this end point

Secondary: Change From Baseline of Upper Leg to Knee to Heel Length Ratio during 6 Months Post Treatment - Cohort 3 and 4

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End point title

Change From Baseline of Upper Leg to Knee to Heel Length Ratio during 6 Months Post Treatment - Cohort 3 and 4 ^[3]

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.

End point type

Secondary

End point timeframe

At month 6 (Day 183)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical Results were summarized by dose cohort and for all cohorts combined.

End point values	Cohorts 3	Cohorts 4
Number of subjects analysed	10	8
Units: ratio
arithmetic mean (standard deviation)
Baseline (n = 10,8)	0.687 ± 0.0268	0.691 ± 0.0847
Change from Baseline to Day 183 (n = 10,8)	0.007 ± 0.0411	-0.006 ± 0.0810

No statistical analyses for this end point

Secondary: Change From Baseline of Upper Leg to Knee to Heel Length Ratio during Entire Study Period - Cohort 3 and 4

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End point title

Change From Baseline of Upper Leg to Knee to Heel Length Ratio during Entire Study Period - Cohort 3 and 4

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.

End point type

Secondary

End point timeframe

At month 24

End point values	Cohorts 3	Cohorts 4
Number of subjects analysed	10	8
Units: ratio
arithmetic mean (standard deviation)
Baseline (n = 10,8)	0.687 ± 0.0268	0.691 ± 0.0847
Change from Baseline to Month 24 (n = 10, 8)	0.010 ± 0.0503	-0.033 ± 0.1065

No statistical analyses for this end point

Secondary: Change From Baseline of Upper Leg Length to Tibial Length Ratio during 6 Months Post Treatment - Cohort 3 and 4

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End point title

Change From Baseline of Upper Leg Length to Tibial Length Ratio during 6 Months Post Treatment - Cohort 3 and 4 ^[4]

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.

End point type

Secondary

End point timeframe

At month 6 (Day 183)

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical Results were summarized by dose cohort and for all cohorts combined.

End point values	Cohorts 3	Cohorts 4
Number of subjects analysed	10	8
Units: ratio
arithmetic mean (standard deviation)
Baseline (n =10,8)	1.107 ± 0.0607	1.061 ± 0.1341
Change from Baseline to Day 183 (n = 10,8)	0.034 ± 0.1048	0.015 ± 0.1571

No statistical analyses for this end point

Secondary: Change From Baseline of Upper Leg Length to Tibial Length Ratio during Entire Study Period - Cohort 3 and 4

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End point title

Change From Baseline of Upper Leg Length to Tibial Length Ratio during Entire Study Period - Cohort 3 and 4

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.

End point type

Secondary

End point timeframe

At month 24

End point values	Cohorts 3	Cohorts 4
Number of subjects analysed	10	8
Units: ratio
arithmetic mean (standard deviation)
Baseline (n = 10,8)	1.107 ± 0.0607	1.061 ± 0.1341
Change from Baseline to Month 24 (n = 10,8)	0.014 ± 0.0888	-0.012 ± 0.1477

No statistical analyses for this end point

Secondary: Change From Baseline of Arm Span to Height Ratio during 6 Months Post Treatment - Cohort 3 and 4

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End point title

Change From Baseline of Arm Span to Height Ratio during 6 Months Post Treatment - Cohort 3 and 4 ^[5]

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.

End point type

Secondary

End point timeframe

At month 6 (Day 183)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical Results were summarized by dose cohort and for all cohorts combined.

End point values	Cohorts 3	Cohorts 4
Number of subjects analysed	10	8
Units: ratio
arithmetic mean (standard deviation)
Baseline (n = 4,7)	0.913 ± 0.0123	0.893 ± 0.0284
Change from Baseline to Day 183 (n= 4,7)	0.007 ± 0.0063	0.001 ± 0.0143

No statistical analyses for this end point

Secondary: Change From Baseline of Arm Span to Height Ratio during Entire Study Period - Cohort 3 and 4

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End point title

Change From Baseline of Arm Span to Height Ratio during Entire Study Period - Cohort 3 and 4

End point description

Efficacy Analysis Population includes all subjects who received at least one dose of study treatment and who had post treatment data for any efficacy endpoint in the corresponding period were included in the Efficacy Analysis and Extension Efficacy Analysis population. Body Proportion ratios assessed includes Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height), Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm (Forearm) Length, Upper to Lower Leg ratio: Upper Leg Length (Thigh) / Knee to Heel Length and Upper Leg Length (Thigh)/ Tibial Leg Length, Arm Span to Height ratio: Arm Span / Standing Height.

End point type

Secondary

End point timeframe

At month 24

End point values	Cohorts 3	Cohorts 4
Number of subjects analysed	10	8
Units: ratio
arithmetic mean (standard deviation)
Baseline (n = 5,8)	0.911 ± 0.0119	0.900 ± 0.0315
Change from Baseline to Month 24 (n = 5,8)	0.000 ± 0.0123	-0.006 ± 0.0290

No statistical analyses for this end point

Secondary: Time to Maximum Observed Concentration (Tmax) of BMN 111 at month 24

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End point title

Time to Maximum Observed Concentration (Tmax) of BMN 111 at month 24

End point description

Pharmacokinetic Parameter Tmax is the time to reach Cmax (maximum observed plasma concentration) PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.

End point type

Secondary

End point timeframe

At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose for month 24.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	6	6	10	8
Units: min
median (full range (min-max))	15.5 (6.00 to 32.0)	17.0 (15.0 to 30.0)	30.0 (15.0 to 88.0)	30.0 (15.0 to 60.0)

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of BMN 111 at month 24

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End point title

Maximum Observed Plasma Concentration (Cmax) of BMN 111 at month 24

End point description

Pharmacokinetic Parameter Cmax is the maximum observed plasma concentration. PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.

End point type

Secondary

End point timeframe

At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose at month 24.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	6	6	10	8
Units: pg/mL
arithmetic mean (standard deviation)	21800 ± 35500	4450 ± 2330	8730 ± 4800	20500 ± 12700

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC(0-t)) of BMN 111 at month 24

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End point title

Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC(0-t)) of BMN 111 at month 24

End point description

Pharmacokinetic parameter (AUC(0-t)) is the Area under the plasma concentration-time curve from time 0 to the time of last measurable concentration. PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.

End point type

Secondary

End point timeframe

At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose at month 24.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	6	6	10	8
Units: pg-min/mL
arithmetic mean (standard deviation)	602000 ± 526000	180000 ± 104000	609000 ± 457000	1730000 ± 936000

No statistical analyses for this end point

Secondary: Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) of BMN 111 at month 24

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End point title

Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) of BMN 111 at month 24

End point description

Pharmacokinetic parameter (AUC0-∞) is the Area under the plasma concentration-time curve from time 0 to infinity. PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.

End point type

Secondary

End point timeframe

At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose at month 24.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	6	6	10	8
Units: pg-min/mL
arithmetic mean (standard deviation)	720000 ± 539000	382000 ± 0.00	643000 ± 470000	1720000 ± 1000000

No statistical analyses for this end point

Secondary: Apparent clearance of BMN 111 (CL/F) at month 24

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End point title

Apparent clearance of BMN 111 (CL/F) at month 24

End point description

Pharmacokinetic parameter (CL/F) is the Apparent clearance of BMN 111. PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.

End point type

Secondary

End point timeframe

At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose at month 24.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	6	6	10	8
Units: mL/min/kg
arithmetic mean (standard deviation)	33.0 ± 23.2	39.3 ± 0.00	31.9 ± 14.8	26.7 ± 21.9

No statistical analyses for this end point

Secondary: Apparent volume of distribution of BMN 111 (Vz/F) at month 24

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End point title

Apparent volume of distribution of BMN 111 (Vz/F) at month 24

End point description

Pharmacokinetic parameter (Vz/F) is the Apparent volume of BMN 111. PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.

End point type

Secondary

End point timeframe

At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose at month 24.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	6	6	10	8
Units: mL/kg
arithmetic mean (standard deviation)	1060 ± 629	1220 ± 0.00	1210 ± 428	1180 ± 472

No statistical analyses for this end point

Secondary: Elimination half-life (t1/2) of BMN 111 at month 24

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End point title

Elimination half-life (t1/2) of BMN 111 at month 24

End point description

Pharmacokinetic parameter (t1/2) is the Elimination half-life PK Analysis Population for each of initial 6-month period and the extension period, all subjects who received at least one dose of study treatment in this study and had any post-treatment PK information in the corresponding period were included in the analysis.

End point type

Secondary

End point timeframe

At pre-dose, 5, 15, 30, 60, 90, 120 and 180 minutes post dose at month 24.

End point values	Cohort 1	Cohort 2	Cohort 3	Cohort 4
Number of subjects analysed	6	6	10	8
Units: min
arithmetic mean (standard deviation)	23.5 ± 2.56	21.5 ± 0.00	29.0 ± 8.05	38.4 ± 14.3

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AbdominalUp to Month 24 � 14 Days

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

Entire Study Period - Cohort 1

Reporting group description

Reporting group title

Entire Study Period - Cohort 2

Reporting group description

Reporting group title

Entire Study Period - Cohort 3

Reporting group description

Reporting group title

Entire Study Period - Cohort 4

Reporting group description

Serious adverse events	Entire Study Period - Cohort 1	Entire Study Period - Cohort 2	Entire Study Period - Cohort 3	Entire Study Period - Cohort 4
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Congenital, familial and genetic disorders
Thyroglossal cyst
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Sleep apnoea syndrome
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillar hypertrophy
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Entire Study Period - Cohort 1	Entire Study Period - Cohort 2	Entire Study Period - Cohort 3	Entire Study Period - Cohort 4
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 8 (87.50%)	8 / 8 (100.00%)	9 / 10 (90.00%)	9 / 9 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Vascular disorders
Hypotension
subjects affected / exposed	5 / 8 (62.50%)	5 / 8 (62.50%)	4 / 10 (40.00%)	2 / 9 (22.22%)
occurrences all number	8	13	4	5
Haematoma
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Hypertension
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Pallor
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Surgical and medical procedures
Ear tube insertion
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	1	1	0
Tooth extraction
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
General disorders and administration site conditions
Injection site reaction
subjects affected / exposed	6 / 8 (75.00%)	7 / 8 (87.50%)	8 / 10 (80.00%)	9 / 9 (100.00%)
occurrences all number	1035	1051	1398	1869
Injection site erythema
subjects affected / exposed	5 / 8 (62.50%)	7 / 8 (87.50%)	9 / 10 (90.00%)	9 / 9 (100.00%)
occurrences all number	76	1231	465	1935
Injection site swelling
subjects affected / exposed	5 / 8 (62.50%)	4 / 8 (50.00%)	5 / 10 (50.00%)	2 / 9 (22.22%)
occurrences all number	32	4	431	28
Injection site urticaria
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	2 / 10 (20.00%)	4 / 9 (44.44%)
occurrences all number	105	3	145	10
Injection site pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 10 (20.00%)	3 / 9 (33.33%)
occurrences all number	0	0	3	60
Pyrexia
subjects affected / exposed	5 / 8 (62.50%)	3 / 8 (37.50%)	5 / 10 (50.00%)	2 / 9 (22.22%)
occurrences all number	5	3	7	3
Injection site bruising
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	11	2	0	2
Fatigue
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	4	1	1	0
Injection site pruritus
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 10 (20.00%)	1 / 9 (11.11%)
occurrences all number	1	0	2	2
Injection site haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 10 (20.00%)	1 / 9 (11.11%)
occurrences all number	0	0	2	2
Application site erythema
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Cyst
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Influenza like illness
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Injection site discolouration
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Injection site induration
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Malaise
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Medical device site reaction
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	2	0	1	0
Hypersensitivity
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	2
Seasonal allergy
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)
occurrences all number	0	0	1	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	5 / 8 (62.50%)	2 / 8 (25.00%)	3 / 10 (30.00%)	4 / 9 (44.44%)
occurrences all number	8	2	5	10
Oropharyngeal pain
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	3 / 10 (30.00%)	0 / 9 (0.00%)
occurrences all number	2	8	6	0
Nasal congestion
subjects affected / exposed	1 / 8 (12.50%)	3 / 8 (37.50%)	0 / 10 (0.00%)	2 / 9 (22.22%)
occurrences all number	1	5	0	3
Rhinorrhoea
subjects affected / exposed	2 / 8 (25.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	2	2	0	1
Epistaxis
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	2	1	0
Sleep apnoea syndrome
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 10 (20.00%)	0 / 9 (0.00%)
occurrences all number	1	0	2	0
Sneezing
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)
occurrences all number	0	0	1	1
Tonsillar hypertrophy
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 10 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0
Asthma
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Nasal dryness
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Rhinitis allergic
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Snoring
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Wheezing
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Psychiatric disorders
Emotional disorder
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	3	0	0
Irritability
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0
Attention deficit/hyperactivity disorder
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Enuresis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Frustration tolerance decreased
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0
Aggression
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0
Investigations
Body temperature increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	3
Eosinophil count increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 10 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	3	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0
Vitamin D decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 10 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0
Blood immunoglobulin E increased
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Respiratory rate increased
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Sleep study abnormal
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	2 / 10 (20.00%)	1 / 9 (11.11%)
occurrences all number	1	5	6	1
Fall
subjects affected / exposed	4 / 8 (50.00%)	0 / 8 (0.00%)	2 / 10 (20.00%)	2 / 9 (22.22%)
occurrences all number	4	0	2	3
Contusion
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	4	2	1	0
Procedural anxiety
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	3	0	0
Limb injury
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	0	1
Procedural pain
subjects affected / exposed	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0
Skin abrasion
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 9 (22.22%)
occurrences all number	0	0	0	2
Thermal burn
subjects affected / exposed	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0
Excoriation
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0
Joint injury
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Laceration
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Meniscus injury
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Muscle strain
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0
Post-traumatic pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Soft tissue injury
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Sunburn
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Wound
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Congenital, familial and genetic disorders
Thyroglossal cyst
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Cardiac disorders
Cyanosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Wolff-Parkinson-White syndrome
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Nervous system disorders
Headache
subjects affected / exposed	4 / 8 (50.00%)	2 / 8 (25.00%)	3 / 10 (30.00%)	3 / 9 (33.33%)
occurrences all number	15	8	13	8
Dizziness
subjects affected / exposed	2 / 8 (25.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	4	1	2	0
Presyncope
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	1	1	0
Syncope
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0
Tremor
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	2
Sinus headache
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Blood and lymphatic system disorders
Lymphadenopathy
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	1	0	1	0
Neutropenia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	1	0	1	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	2 / 8 (25.00%)	4 / 8 (50.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)
occurrences all number	2	6	2	3
Ear swelling
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	0	0
Otorrhoea
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	1	1	0
Middle ear effusion
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0
Tympanic membrane hyperaemia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Eye disorders
Eye pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	1	0	1	0
Eye discharge
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Eye inflammation
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Eye irritation
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Hypermetropia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Gastrointestinal disorders
Vomiting
subjects affected / exposed	2 / 8 (25.00%)	2 / 8 (25.00%)	2 / 10 (20.00%)	3 / 9 (33.33%)
occurrences all number	6	5	6	5
Nausea
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)
occurrences all number	3	2	1	2
Abdominal pain upper
subjects affected / exposed	2 / 8 (25.00%)	3 / 8 (37.50%)	1 / 10 (10.00%)	1 / 9 (11.11%)
occurrences all number	2	3	1	1
Diarrhoea
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 10 (10.00%)	2 / 9 (22.22%)
occurrences all number	2	1	1	3
Abdominal pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	1 / 9 (11.11%)
occurrences all number	0	1	3	1
Dental caries
subjects affected / exposed	3 / 8 (37.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	0	0	0
Dyspepsia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0
Faeces discoloured
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0
Malpositioned teeth
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0
Mouth ulceration
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	2
Toothache
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0
Aphthous ulcer
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Gastritis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Gingival bleeding
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Oral pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Parotid gland enlargement
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 8 (12.50%)	2 / 8 (25.00%)	2 / 10 (20.00%)	1 / 9 (11.11%)
occurrences all number	1	4	2	1
Dermatitis
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	2	3	0
Dry skin
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	2	1	0
Pruritus
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)
occurrences all number	1	0	1	1
Erythema
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	1	0	1	0
Rash generalised
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	1	0	1	0
Rash pruritic
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	2
Acne
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Miliaria
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Skin exfoliation
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Skin striae
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 10 (10.00%)	4 / 9 (44.44%)
occurrences all number	2	1	1	8
Arthralgia
subjects affected / exposed	3 / 8 (37.50%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)
occurrences all number	4	0	2	2
Back pain
subjects affected / exposed	1 / 8 (12.50%)	3 / 8 (37.50%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	2	3	1	0
Neck pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 10 (10.00%)	1 / 9 (11.11%)
occurrences all number	1	0	2	1
Groin pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	0	0	0
Joint range of motion decreased
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	2
Bone pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Muscle spasms
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Myalgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Infections and infestations
Nasopharyngitis
subjects affected / exposed	1 / 8 (12.50%)	4 / 8 (50.00%)	5 / 10 (50.00%)	2 / 9 (22.22%)
occurrences all number	1	11	12	9
Ear infection
subjects affected / exposed	2 / 8 (25.00%)	3 / 8 (37.50%)	2 / 10 (20.00%)	2 / 9 (22.22%)
occurrences all number	4	12	3	7
Upper respiratory tract infection
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	3 / 10 (30.00%)	2 / 9 (22.22%)
occurrences all number	1	4	7	5
Otitis media
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	2 / 10 (20.00%)	3 / 9 (33.33%)
occurrences all number	1	1	3	5
Viral upper respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	3 / 8 (37.50%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	7	0	1
Gastroenteritis viral
subjects affected / exposed	2 / 8 (25.00%)	2 / 8 (25.00%)	0 / 10 (0.00%)	2 / 9 (22.22%)
occurrences all number	2	2	0	2
Viral infection
subjects affected / exposed	3 / 8 (37.50%)	0 / 8 (0.00%)	2 / 10 (20.00%)	1 / 9 (11.11%)
occurrences all number	3	0	2	1
Gastroenteritis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	3	0	0	1
Bronchitis
subjects affected / exposed	2 / 8 (25.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	2	0	1	0
Sinusitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	2	0	1	0
Conjunctivitis
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	0	0
Influenza
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	2 / 9 (22.22%)
occurrences all number	0	0	0	2
Otitis externa
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	0	1
Pharyngitis streptococcal
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 10 (20.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0
Rhinitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0
Acute sinusitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Atypical pneumonia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Croup infectious
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Eye abscess
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Gastrointestinal viral infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Incision site infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Onychomycosis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Pharyngitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Rash pustular
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Respiratory tract infection
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Scarlet fever
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 10 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1
Tonsillitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Tooth abscess
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0
Varicella
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 10 (10.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0
Vitamin D deficiency
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 10 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

03 Jun 2014

Amendment 1 established an optional, open-label extension phase of approximately 18 months to commence at the end of the initial phase of the study, making a total study duration of approximately 25 months, including a 1-month safety follow-up visit. The rationale for extending this Phase 2 study was to assess the long-term safety and tolerability of BMN 111 in children with ACH; and to assess longer-term effects of BMN 111 on the growth in these children.

08 May 2015

Amendment 2 established higher doses in 2 additional cohorts in the initial 6 months of the study. Cohort 4 and 5 daily doses of 30 μg/kg and up to 60 μg/kg BMN 111, respectively, were selected with the intent to achieve exposures expected to result in further increases in growth velocity in children with ACH with an acceptable safety profile. In addition, baseline hip assessments and hip monitoring to screen for effects on hip joints and/or mobility were added for all cohorts.

26 Oct 2015

Amendment 3 added a thyroid function test at the Month 24 visit to assess any changes over the course of the open-label extension phase of 111-202. This amendment also specified that the assessment at Month 24 would serve as the baseline/screening assessments for entry into 111-205 and waived the safety follow-up visit at Month 25 if a subject enrolled in 111-205 at the Month 24/Study Completion Visit. These changes ensured uninterrupted transition of subjects who complete 111-202 into 111-205.

22 Aug 2016

Amendment 4 removed Cohort 5 based on the 6-month data from Cohort 4. Preliminary PK data from Cohort 4 (30 μg/kg daily) showed a greater than dose proportional increase in BMN 111 exposure, with mean plasma maximum observed plasma concentration (Cmax) and area under the time-concentration curve from zero to the last quantifiable concentration (AUC0-t) values at the target exposure previously expected to require daily doses up to 60 μg/kg. A marginal improvement was observed in both absolute AGV and change from baseline AGV in Cohort 4 (BMN 111 daily at 30 μg/kg) after 6 months of BMN 111 treatment when compared with Cohort 3 (BMN 111 daily at 15 μg/kg). Given this observation, higher doses of BMN 111 were not expected to demonstrate an improved benefit/risk profile. Thus, Cohort 5 (with daily dosing up to 60 μg/kg) was not pursued.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 111 in Children with Achondroplasia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of subjects with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs)

Primary: Number of subjects with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs)

Secondary: Change From Baseline of Annualized Growth Velocity (AGV) during Initial 6-Month

Secondary: Change From Baseline of Annualized Growth Velocity (AGV) during Initial 6-Month

Secondary: Change From Baseline of Annualized Growth Velocity (AGV) during Entire Study Period Cohort 3 and 4

Secondary: Change From Baseline of Annualized Growth Velocity (AGV) during Entire Study Period Cohort 3 and 4

Secondary: Change From Baseline of Annualized Growth Velocity (AGV) during Entire Study Period - Cohort 1 and 2 Switchers

Secondary: Change From Baseline of Annualized Growth Velocity (AGV) during Entire Study Period - Cohort 1 and 2 Switchers

Secondary: Change From Baseline of Z-Scores Using CDC Reference Standard during 6-Months Post-Treatment

Secondary: Change From Baseline of Z-Scores Using CDC Reference Standard during 6-Months Post-Treatment

Secondary: Change From Baseline of Height Z-Scores Using CDC Reference Standard during Entire Study Period - Cohort 3 and 4

Secondary: Change From Baseline of Height Z-Scores Using CDC Reference Standard during Entire Study Period - Cohort 3 and 4

Secondary: Change From Baseline of Height Z-Scores Using Non-ACH References during Entire Study Period - Cohort 1 and 2 Switchers

Secondary: Change From Baseline of Height Z-Scores Using Non-ACH References during Entire Study Period - Cohort 1 and 2 Switchers

Secondary: Change From Baseline of Weight Z-Scores Using Non-ACH References during Entire Study Period - Cohort 1 and 2 Switchers

Secondary: Change From Baseline of Weight Z-Scores Using Non-ACH References during Entire Study Period - Cohort 1 and 2 Switchers

Secondary: Change From Baseline of Upper to Lower Body Ratios during 6 Months Post Treatment

Secondary: Change From Baseline of Upper to Lower Body Ratios during 6 Months Post Treatment

Secondary: Change From Baseline of Upper to Lower Body Ratios during Entire Study Period - Cohort 3 and 4

Secondary: Change From Baseline of Upper to Lower Body Ratios during Entire Study Period - Cohort 3 and 4

Secondary: Change From Baseline of Upper Arm to Lower Arm Length Ratio during 6 Months Post Treatment - Cohort 3 and 4

Secondary: Change From Baseline of Upper Arm to Lower Arm Length Ratio during 6 Months Post Treatment - Cohort 3 and 4

Secondary: Change From Baseline of Upper Arm to Lower Arm Length Ratio during Entire Study Period - Cohort 3 and 4

Secondary: Change From Baseline of Upper Arm to Lower Arm Length Ratio during Entire Study Period - Cohort 3 and 4

Secondary: Change From Baseline of Upper Leg to Knee to Heel Length Ratio during 6 Months Post Treatment - Cohort 3 and 4

Secondary: Change From Baseline of Upper Leg to Knee to Heel Length Ratio during 6 Months Post Treatment - Cohort 3 and 4

Secondary: Change From Baseline of Upper Leg to Knee to Heel Length Ratio during Entire Study Period - Cohort 3 and 4

Secondary: Change From Baseline of Upper Leg to Knee to Heel Length Ratio during Entire Study Period - Cohort 3 and 4

Secondary: Change From Baseline of Upper Leg Length to Tibial Length Ratio during 6 Months Post Treatment - Cohort 3 and 4

Secondary: Change From Baseline of Upper Leg Length to Tibial Length Ratio during 6 Months Post Treatment - Cohort 3 and 4

Secondary: Change From Baseline of Upper Leg Length to Tibial Length Ratio during Entire Study Period - Cohort 3 and 4

Secondary: Change From Baseline of Upper Leg Length to Tibial Length Ratio during Entire Study Period - Cohort 3 and 4

Secondary: Change From Baseline of Arm Span to Height Ratio during 6 Months Post Treatment - Cohort 3 and 4

Secondary: Change From Baseline of Arm Span to Height Ratio during 6 Months Post Treatment - Cohort 3 and 4

Secondary: Change From Baseline of Arm Span to Height Ratio during Entire Study Period - Cohort 3 and 4

Secondary: Change From Baseline of Arm Span to Height Ratio during Entire Study Period - Cohort 3 and 4

Secondary: Time to Maximum Observed Concentration (Tmax) of BMN 111 at month 24

Secondary: Time to Maximum Observed Concentration (Tmax) of BMN 111 at month 24

Secondary: Maximum Observed Plasma Concentration (Cmax) of BMN 111 at month 24

Secondary: Maximum Observed Plasma Concentration (Cmax) of BMN 111 at month 24

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC(0-t)) of BMN 111 at month 24

Secondary: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Measurable Concentration (AUC(0-t)) of BMN 111 at month 24

Secondary: Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) of BMN 111 at month 24

Secondary: Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) of BMN 111 at month 24

Secondary: Apparent clearance of BMN 111 (CL/F) at month 24

Secondary: Apparent clearance of BMN 111 (CL/F) at month 24

Secondary: Apparent volume of distribution of BMN 111 (Vz/F) at month 24

Secondary: Apparent volume of distribution of BMN 111 (Vz/F) at month 24

Secondary: Elimination half-life (t1/2) of BMN 111 at month 24

Secondary: Elimination half-life (t1/2) of BMN 111 at month 24

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 111 in Children with Achondroplasia